Cardiac stem cells delivered intravascularly traverse the vessel barrier, regenerate infarcted myocardium, and improve cardiac function

Abstract

The ability of cardiac stem cells (CSCs) to promote myocardial repair under clinically relevant conditions (i.e., when delivered intravascularly after reperfusion) is unknown. Thus, rats were subjected to a 90-min coronary occlusion; at 4 h after reperfusion, CSCs were delivered to the coronary arteries via a catheter positioned into the aortic root. Echocardiographic analysis showed that injection of CSCs attenuated the increase in left ventricular (LV) end-diastolic dimensions and impairment in LV systolic performance at 5 weeks after myocardial infarction. Pathologic analysis showed that treated hearts exhibited a smaller increase in LV chamber diameter and volume and a higher wall thickness-to-chamber radius ratio and LV mass-to-chamber volume ratio. CSCs induced myocardial regeneration, decreasing infarct size by 29%. A diploid DNA content and only two chromosomes 12 were found in new cardiomyocytes, indicating that cell fusion did not contribute to tissue reconstitution. In conclusion, intravascular injection of CSCs after reperfusion limits infarct size, attenuates LV remodeling, and ameliorates LV function. This study demonstrates that CSCs are effective when delivered in a clinically relevant manner, a clear prerequisite for clinical translation, and that these beneficial effects are independent of cell fusion. The results establish CSCs as candidates for cardiac regeneration and support an approach in which the heart's own stem cells could be collected, expanded, and stored for subsequent therapeutic repair. myocardial infarction ͉ myocardial regeneration W ith the recent surge of interest in cardiac regenerative therapies for patients with acute myocardial infarction (MI) (1), the identification of clinically applicable strategies is of paramount importance. Several cell types have been used in an effort to reconstitute dead myocardium. Among them, endothelial progenitor cells and bone marrow-derived cells have been the most successful (2-6). However, preliminary long-term studies with bone marrow-derived cells indicate that the new myocytes do not acquire the adult phenotype but resemble neonatal cells, which die with time by apoptosis (P.A., unpublished data). Intense efforts continue to focus on identifying an effective cell population and an effective mode of delivery.The discovery that the adult heart contains a pool of cardiac stem cells (CSCs) that can replenish the cardiomyocyte population and generate coronary vessels (7-12) has dramatically changed the traditional view of the heart as a postmitotic organ. Because of its natural role in regeneration of cardiac cells, the endogenous CSC appears to be the ideal cell for myocardial repair. Recent studies have shown that when c-kit POS CSCs are injected directly into the myocardium adjacent to an infarct produced by a permanent coronary occlusion, they migrate to the infarct and reconstitute part of the dead tissue, reducing infarct size and ameliorating cardiac function in rats (9) and mice (12). In contrast, i.v. injection of CSCs in mice subje...

Repeated Administrations of Cardiac Progenitor Cells Are Superior to a Single Administration of an Equivalent Cumulative Dose

“…Serial echocardiograms were obtained at 5 time points: baseline (3 days before coronary artery occlusion), 30 days after MI (before the first treatment), 35 days after the first treatment (before the second treatment), 35 days after the second treatment (before the third treatment), and 35 days after the third treatment (before euthanasia; Figure 1). The echocardiographic studies were performed as described3, 7, 8, 9, 10 using a Vevo 2100 Imaging System equipped with a 20‐MHz transducer.…”

“…The hemodynamic studies were conducted 35 days after the third treatment, just before euthanasia (Figure 1). The protocol has been described previously 3, 7, 8, 9, 10…”

Stem cells in the heart: What's the buzz all about?—Part 1: Preclinical considerations

“…Studies have shown that c-Kit + cardiac stem cells isolated from the adult rat heart home to infarcted areas when delivered via the aortic root during a reperfusion protocol, improving LVEF 5 weeks post-MI (LVEF ≈ 48% treated vs LVEF ≈ 40% control [P <.05] compared to baseline LVEF ≈ 75%), and regenerate muscle and vessels in the absence of cell fusion as demonstrated by the presence of at most two copies of chromosome 12 (detected by fluorescence in situ hybridization) in newly formed green fluorescent protein (GFP)-positive cardiomyocytes. 10 This study represents an important step toward clinically relevant application of cardiac stem cells.…”

Thérapies cellulaires pro-angiogéniques dans le traitement des pathologies ischémiques

“…Elle permettrait notamment de comprendre l'observation d'un nombre restreint de cardiomyocytes en mitose et la présence de cellules progénitrices vasculaires dans le tissu cardiaque, dont l'origine, médullaire ou endogène cardiaque, est très débattue. Enfin, ces cellules souches cardiaques pourraient servir de base à des thérapies cellulaires développées pour le traitement des pathologies cardiaques [11].…”